AMP activated protein kinase (AMPK) is the central component of a signaling system that functions to maintain cellular energy balance in response to stresses that deplete intracellular ATP. It is often referred to as a "metabolic master switch" because of the central role that it plays in the maintenance of metabolic homeostasis. AMPK activity has a strong influence on the regulation of whole body glucose metabolism and it may also play a role in the development of type-2 diabetes. It has recently been reported that some of the antidiabetic activities of the drug metformin and the hormone adiponectin may be mediated by activation of AMPK in the liver, suggesting a potential link between AMPK and hepatic glucose metabolism. We have recently demonstrated that the transcription factor HNF4alpha, a well-characterized regulator of metabolic gene expression in the liver, is inhibited by AMPK mediated phosphorylation on serine-304. HNF4alpha is known to play an important role in the expression of liver genes involved in regulating hepatic glucose production, a key contributor to normal and diabetic whole body glucose homeostasis. The central hypothesis of the work proposed here is that an AMPK-HNF4alpha signaling pathway in the liver mediates important metabolic effects of AMPK. The overall goals of this proposal are to characterize the molecular details of this proposed AMPK-HNF4alpha signaling pathway and to determine the extent to which it influences gene expression and metabolism in normal and diabetic liver. In addition, the possibility that AMPK mediated phosphorylation of HNF4alpha contributes to the hepatic effects of metformin and adiponectin will be explored. Results from these studies will provide a clearer understanding of the functional relationship between HNF4alpha and AMPK and a more complete picture of the physiological role that these two important proteins play in the liver.